1,2,3,4,9,12-Hexahydrophenanthrenes

ABSTRACT

New compounds of the 1,2,3,4,9,12-hexahydrophenanthrene class, useful as estrogenic and anti-fertility agents, and methods for their preparation. 1 Alpha -Ethyl-2 Alpha -carboxy-2 Beta methyl-7-methoxy-1,2,3,4,9,12-hexahydrophenanthrene is exemplified as illustrative of the class.

United States Patent Edwards et al.

l,2,3,4,9,IZ-HEXAHYDROPHEN ANTH- RENES Inventors: John A. Edwards, LosAltos; John H. Fried, Palo Alto, both of Calif.

Assignee: Syntex Corporation, Apartado,

Panama, Panama Filed: Mar. 17, 1912 Appl. No.: 235,808

Related U.S. Application Data Division of Ser. No. 883,582, Dec. 9,1969, Pat. No. 3,681,427.

U.S. Cl 260/613 R, 260/345.8, 424/308, 424/311, 260/345.9, 424/312,424/341, 260/347.4, 424/346, 260/347.8, 260/410.5, 260/457, 260/468 R,260/468 G, 260/468.5, 260/473 F, 260/476 C, 260/479 R, 260/479 S,260/482 R-, 260/484 R, 260/487, 260/488 B, 260/488 CD, 260/5l4.5,260/520,

260/520 R, 260/600, 260/611 F, 260/6l7.5, 260/930, 260/951, 260/952,260/953,

Int. Cl. C07c 171/07 [58] Field of Search 260/396 R, 396 N, 613 R,

260/479 R, 488 CD, 617.5, 476 C, 410. 487, 482 R, 484, 345.8, 345.9,347.4, 347.8, 468 R, 468 G [56] References Cited UNITED STATES PATENTS2,938,056 5/1960 Nathan et a1. 260/613 R 3,275,691 9/1966 Goldberg eta1. 260/613 R 3,483,226 12/1969 Baran 260/613 R 3,716,578 2/1973 Johnk260/613 R Primary Examiner-Vivian Garner Attorney, Agent, or Firm Tom M.Moran; Joseph J. Hirsch; Walter H. Dreger [57] ABSTRACT New compounds ofthe l,2,3,4,9,12-hexahydrophenanthrene class, useful as estrogenic andantifertility agents, and methods for their preparation. la-Ethyl-Za-carboxy-ZB-methylJ-methoxy-1,2 ,3,4,9,12- hexahydrophenanthreneis exemplified as illustrative of the class.

8 Claims, No Drawings 1 l,2,3,4,9, IZ-HEXAHYDROPHENANTHRENES In theforegoing and succeeding formulas,

R is methyl or ethyl;

R is carboxy and the alkali metal salts thereof, carb (lower)-alkyloxy,formyl, or hydroxymethyl and the conventional hydrolyzable esters andethers thereof;

R is methyl or ethyl;

R is lower alkyloxy, hydroxy or the conventional hydrolyzable esters andethers thereof; and

R is hydrogen or methyl.

In the presentspecification and claims, the term lower alkyloxy denotesthe group OAlkyl, alkyl being a straight or branched chain saturatedhydrocarbon group containing from I to 6 carbon atoms, inclusive, suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,pentyl, amyl, hexyl, and the like. The expression conventionalhydrolyzable esters and ethers, as used herein, refers to thosephysiologically acceptable hydrolyzable ester groups and labile ethergroups conventionally employed in the pharmaceutical art such asacetate, propionate, butyrate, trimethylacetate, valerate,methylethylacetate, caproate, butylacetate, 3-methylpentanoate,enanthate, caprylate, triethylacetate, pelargonate, decanoate,undecanoate, benzoate, phenylacetate, diphenylacetate,cyclopentylpropionate, methoxyacetate, aminoacetate,diethylaminoacetate, trichloroacetate, B-chloropropionate, bicyclo[2.2.2]octane-l-carboxylate, adamantoate, dihydrogen phosphate, dibenzylphosphate, sodium ethyl phosphate, sodium sulfate, sulfate,tetrahydropyran-Zyl ether, tetrahydrofuran-Q-yl ether,4-methoxytetrahydropyran-4-yl ether, cyclopentyl ether, and the like.The expression carboxy" denotes the -CO H group and formyl the --Cl-IOgroup.

In the present specification and claims, the wavy lines (in at the C-lposition of the phenanthrene nucleus indicates the configuration alphaor beta or mixtures thereof. Thus, the compounds of the presentinvention can exist in two d and two lforms, that is, d-cis, dtrans,l-cis, and l-trans. In addition, two racemates are possible, that is,dl-cis and dl-trans. While each or mixtures are included within thescope hereof, the dlcis racemate is preferred.

With respect to the other center of symmetry present at the C-12position, the process of the present invention by which the compoundsare prepared generates both the individual alpha and beta isomers ormixtures thereof. The individual 12a and 12B isomers are separable bychromatography and each and the mixture thereof are included within thescope of the present invention.

For the purposes of the present invention, the conventional numbering ofthe various carbon positions on the phenanthrene nucleus is employed, asdepicted by the following partial formula:

For example, as used herein, the position of the R substituent isdesignated and defined as the C-10 ring position.

The compounds of the present invention possess estrogenic andanti-fertility activity. They are accordingly useful in replacementtherapy for estrogen deficiencies and in the control and regulation offertility and in the management of various menstrual disorders and are,employed in accordance with these uses in the same manner as knownestrogenic and anti-fertility agents. Thus, they can be administered inconjunction with one or more pharmaceutically non-toxic excipients,whether orally or parenterally, and at dosage levels appropriate for thecondition being treated or effect desired, the most favorable dosagebeing determinable by one of ordinary skill in the art taking intoconsideration the particular condition being treated and the observedresponse to treatment. Useful pharmaceutical excipients, solid orliquid, include water, polyalkylene glycols, vegetable oils, lactose,talc, magnesium stearate, gelatin, starches, flavoring agents and thelike. In general, the compounds of the present invention are used in theadopted manner customary with compounds having like utility.

The compounds of the present invention are prepared in accordance withthe following reaction sequence of partial formulas:

sf m

(III) In the above and succeeding formulas, R is as defined by R,exclusive of hydroxy and the esters thereof.

With reference to the reaction scheme outlined above, the pentaenestarting material (I) is reduced with an alkali metal such as sodium,potassium and lithium and a lower monohydric alcohol in a lower alkylamine or diamine, for example, methyl amine, diethyl amine, and the likeor in liquid ammonia to obtain the triene intermediate compound (II).The triene intermediate (II) is aromatized such as with pyridiniumhydrobromide perbromide to obtain the final product tetraene (Ill).

The first step reduction involves reacting a l,2,3,4-tetrahydrophenanthrene compound together with sodium, potassium, orlithium metal and a lower monohydric alcohol in a lower alkyl amine ordiamine, for example, methyl amine, diethyl amine, and the like or inliquid ammonia. Suitable lower monohydric alcohols include thosestraight or branched alkanols containing from I to 6 carbon atoms suchas methanol, ethanol, n-propanol, isopropanol, n-butanol, sec.-butanol,isobutanol, t-butanol, n-amyl alcohol, and n-hexanol. The

. reaction is conveniently conducted in organic liquid reaction media inadmixture with the alcohol. Suitable media include the common organicsolvents such as tetrahydrofuran, dioxane, toluene, benzene, n-hexane,diethyl ether, glyme, diglyme, and the like. The reaction is conductedat temperatures ranging from about 80C. to about C. and, preferably, atthe boiling point of the reaction mixture and under reflux and for aperiod of time sufficient to complete the reaction ranging from about 1hour to about 14 days.

The second step aromatization involves reacting a l,-2,3,4,5,8,9,l2-octahydrophenanthrene compound together with pyridiniumhydrobromide perbromide. This reaction is conveniently conducted inorganic liquid reaction media. Suitable media include those listedhereinabove which are useful in the reduction step. The reaction isconducted at temperatures ranging from about 80C. to about 25C. or moreand for a period of time sufficient to complete the reaction rangingfrom about 1 minute to about 12 hours.

In carrying out these reactions, the reactants are contacted andmaintained together in any convenient order or fashion. They are thenmaintained within or about the cited temperature range for a period oftime sufficient to produce the product. Following the respectivereaction, the product is recovered and isolated from the reactionmixture following conventional techniques such as decantation,filtration, distillation, extraction, evaporation, and chromatography.

The given reactions consume the respective reactants in the ratio of onemole of starting compound per four moles of alkali metal and one mole ofintermediate triene compound per mole of pyridinium hydrobromideperbromide. However, the amounts of the reactants to be employed are notcritical, some of the desired prod not being obtained when employing anyproportions thereof. In the preferred embodiments hereof, theappropriate reactants are employed in amounts ranging from about fourmoles to about one hundred moles of the alkali metal per mole ofstarting compound, the am monia or amine being employed in large excess,and amounts ranging from about 0.9 moles to about 1.5 moles ofpyridinium hydrobromide pe'rbromide per mole of starting compound.

Although under the conditions of this process, the triene intermediate(ll) is obtained directly upon reduction of (I), it is possible, ifdesired, to obtain and isolate a tetraene derivative of partial formula(I-a) by reduction of compound (I) as described. This compound can beisolated and reduced further as described to obtain the trieneintermediate (ll) by way of twostep methodology.

The following depiction provides more detailed reference to the mannerby which the compounds hereof are prepared.

In the above, each ofR, R, R R and R are as defined hereinabove and R islower alkyl; R is a conventional hydrolyzable ether; and R is aconventional hydrolyzable ester or ether.

By way of further explanation of the processes hereof by which thepresent compounds are prepared, the above depiction represents thevarious useful sequences In the acid series (C-2a), the sequence offormula l 2 3 is employed to arrive at the C-7 ether final products. Inthe preparation of the corresponding 7-hydroxy compounds (formula 4),the C-7 substituent (R) preferably is, or is converted to, thetetrahydropyran-2-yloxy ether which is cleaved upon reaction withlithium iodide in collidine at about 180C. (See Harrison, ChemicalCommunications, No. 11, p. 616 (1969) or with an 80% oxalic acid inaqueous methanol solution at room temperature or with 80% aqueous aceticacid at room temperature. The C-7 esters are derived from the C7 hydroxycompounds.

The acids (formula 3) are also useful for the preparation of thecorresponding esters (formula 5) via the intermediate acid chloride andappropriate alcohol. The corresponding 7-hydroxy derivatives of thelatter esters (formula 4; R carb(lower)alkyloxy) are preferablyobtainable through the 7-tetrahydropyran 2-yloxy compounds, as describedabove.

A similar sequence follows for the preparation of the hydroxymethyl (Rcompounds (formula 8). In this instance, a 2-carb(lower)alkyloxy ester(formula 6) can be employed and reduced in the first step to thehydroxymethyl grouping (formula 7). The hydroxymethyl products (formula8) can be conventionally esterified or etherified (formula 13) and theesters or ethers converted to the corresponding 7-hydroxy compounds(formula 4; R conventional hydrolyzable ester or ether of hydroxymethyl)preferably through the 7-tetrahydropyran-Z-yloxy derivatives, asdescribed above. the hydroxymethyl products (formula 8) can also beconverted to the corresponding 7-hydroxy compounds (formula 4; R=hydroxymethyl or oxidized to the aldehydes (formula 9) with chromicacidin pyridine. The aldehydes can be further oxidized to the acids (formula3) or converted to the 7-hydroxy compound (formula 4; R formyl),preferably through the 7-tetrahydropyranyl ether.

Alternatively, the ester starting compounds (formula 6) can be reducedby reaction with lithium aluminum hydride (THF) to form thecorresponding hydroxymethyl compounds (formula 10). These can be conventionally etherified (formula 1 l or they can be converted asdescribed above to the products (formulas 8 and 13). These products are,in turn, convertable to the corresponding 7-hydroxy compounds (formula4), as described above.

The process of the present invention can be practiced upon startingmaterials bearing the substituents defined by R, R, R R and R Inaccordance withordinary level of skill in the art, certain of thesubstituents are introduced at a time subsequent to the principalreactions in order to avoid chemical interference or competition. Thus,the C-7 hydroxy andl ester compounds are .prepared as last steps as setforth above. The C-Za esoff)-..

wherein R is lower alkyloxy or a conventional hydrolyzable ether; R ismethyl or ethyl;

R is carboxy, hydroxymethyl and the conventional hydrolyzable ethersthereof; R is methyl or ethyl; and R is hydrogen or methyl; are novelcompounds of the present invention useful as intermediates, as hereinset forth, in the preparation of l,2,3,4,9, l 2-hexahydrophenanthreneproducts hereof. The novel compounds of the present invention of theformula:

l l (w to prepare the corresponding compound of partial formula (II): gQ

ha k/ (II) and aromatizing the compound of formula (II) wherein, R is Rexclusive of hydroxy or a conventional hydrolyzable ester thereof;followed by, in optional order and to the extent desired or required:

1. cleaving any ester or ether group to the corresponding alcohol,

2. converting any carboxylic acid to the corresponding ester,

3. converting any carboxylic acid to the corresponding salt,

4. reducing any ester to the corresponding alcohol,

5. hydrolyzing any acid ester to the corresponding acid,

6. oxidizing any alcohol to the corresponding aldehyde,

7. oxidizing any aldehyde to the corresponding acid,

8. esterifying any hydroxyl group, and

9. etherifying any hydroxyl group,

The l,2,3,4-tetrahydrophenanthrene starting compounds hereof are knownin the art or can be prepared in accordance with known processes. See,for example, Helv. Chim. Acta. 28, 1506 (1945) and Helv. Chim.

Acta. 30, 777 (i947) and U.S. Pat. application by Edwards Serial No.589,494, filed Oct. 26, 1966 for Ethers Containing a PhenanthreneNucleus, and the references cited in each, and Medicinal Chemistry, Vo-

Ilumne ll, John Wiley and Sons, Inc., New York, 1956.

Thus, for further example, preparation of the ethers of thehydroxymethyl compounds follows upon etherification with dihydropyran(for the tetrahydropyran-Z-yl ethers and dihydrofuran (for thetetrahydrofuran-2-yl ethers) and 4-methoxy-5,6-dihydro-2H-pyran (for the4-methoxytetrahydropyran-4-yloxy ethers) with acid catalyst in inertsolvent. Cyclopentyl ethers are prepared upon reaction of the hydroxycompound with sodium hydride and Cyclopentyl bromide. The correspondingesters are prepared by reacting the hydroxymethyl compound with ahydrocarbon carboxylic acid anhydride in the presence of pyridine.

The C-lO methyl starting compounds are prepared in accordance with theprocedure described in U.S. Pat. Application Ser. No. 638,648, filed May15, 1967 by Edwards and Fried for Phenanrhrene-2-Carb0xy1ic Acids, whichis hereby incorporated by reference. This ,method involves reacting a2-(3-methyl-l,2,3,4-tetrahydronaphthyliden)-ethyl isothiouronium acetatetogether with a tetronic acid in an aqueous organic solution at aboutroom temperature to prepare the corresponding a-[2-(3-methyl-l,2,3,4-tetrahydronaphthaliden)-ethyl]-tetronic acid compound. Thiscompound is then contacted with a strong acid optionally in an organicsolvent at a temperature of from about room temperature to about refluxto prepare the corresponding 7-methyll 6-oxaestra-l ,3,5( lO),8,l4-pentaen-l7-one steroid. Dehydrogenation thereof with palladium catalystforms the corresponding 6,7- dehydro derivative thereof or treatment ofthe steroid with an alkali metal hydroxide aqueous organic solution atabout room temperature prepares the correspondingl-acetyl-l0-methyl-l,2,3,4- tetrahydrophenanthrene-2-carboxylic acidalkali metal salt. This can be subjected to carbonyl reduction andthence converted to the acid ester with an alkyl iodide which can beconverted to the free acid upon base hydrolysis.

Representative starting compounds are the following:

I[3,2B-dimethyl-2a-carboxy-7-methoxy-l ,2,3,4-tetrahydrophenanthrene,

la-ethyl-Za-carbomethoxy-2l3-methyl-7-ethoxyl 0- methyl-l ,2,3,4-tetrahydrophenanthrene,

la-methyl-Za-hydroxymethyl-2B-ethyl-7-methoxy-1,2,3,4-tetrahydrophenanthrene,

lB,2B-diethyl-2a-tetrahydropyran-2-yloxymethyl-7- cyclopentyloxy-l,2,3,4-tetrahydrophenanthrene,

lB,2,8lO-trimethyl-2a-carboxy-7-methoxy-, l,2,3,4-tetrahydrophenanthrene,

la-ethyl-Za-carboethoxy-2B-methyl-7- tetrahydropyran-Z-yloxy-l,2,3,4-tetrahydrophenanthrene,

la,lO-dimethyl-Za-hydr0xymethyl-2B-ethyl-7- ethoxy-l ,2,3,4-tetrahydrophenanthrene,

la,2/3-diethyl-2a-cyclopentyloxymethyl-7- tetrahydropyran-2 -yloxy-l,2,3,4-tetrahydrophenanthrene,

lB-methyl-2oz-carboxy-2,B-ethyl-7-n-propyloxyl,2,3,4-tetrahydrophenanthrene,and

1B-ethyl-Za-tetrahydropyran-Z -yloxymethyl-2B, l O-dimethyl-7-tetrahydropyran-2'-yloxy-l ,2,3,4-tetrahydrophenanthrene.

tetrahydrophenanthrene The following preparation and examples furtherillustrate the manner by which the present invention can be practicedand represent, in one aspect, the best mode for carrying out theinvention. As such, however, they should be construed merely asillustrative and not as limitative upon the overall scope hereof.

PREPARATION l A solution of l g. of 3-methoxybenzoic acid in 50 ml. ofbenzene is treated with 2 g. of thionyl chloride. The mixture is heatedat reflux under anhydrous conditions for 2 hours and then evaporatedunder reduced pressure. The residue is dissolved in 20 ml. of benzeneand this solution is evaporated to dryness to yield 3- methoxybenzoylchloride.

A solution of 1 g. of the latter compound in 50 ml. of anhydrous etheris heated to reflux and a solution of 5 g. of diethyl cadmium and 50 ml.of anhydrous ether is added. After being heated to reflux for 20 hoursthe mixture is extracted with ether. These extracts are washed withwater to neutrality and evaporated to yield 3-methoxy propiophenone.

A mixture of l g. of the latter compound and 0.5 g. of glyoxylic acid ina solution of 0.5 g. of potassium hydroxide in l ml. of water and I0 ml.of ethanol is allowed to stand at room temperature for a period of [8hours. The solid which forms is collected by filtration, washed withwater and dried to yield 3-(3'-methoxybenzoyl)-2-butenoic acid.

A suspension of 0.5 g. of palladium-on-charcoal catalyst in 50 ml. ofmethanol is hydrogenated for 30 minutes. A solution of l g. of thelatter compound and 200 ml. of methanol is added and hydrogenated withagitation until the uptake of hydrogen has ceased. The catalyst isremoved by filtration and the solution is evaporated to yield3-(3-methoxybenzoyl) butanoic acid.

A mixture of l g. of the latter compound, 2 g. of hydrazine hydrate, 1.2g. of potassium hydroxide, 1.2 ml.

of water and 1.2 ml. of diethylene glycol is heated for 45 minutes atreflux, then in an open flask until the temperature of the reactionmixture is 200C, and finally for an additional 2 hours at reflux. Themixture is cooled, water added and the product isolated by extractionwith ether. These extracts are dried over sodium sulfate and evaporatedto yield 3-(3'- methoxybenzyl) butanoic acid.

A mixture of l g. of the latter material in 10 ml. of polyphosphoricacid is heated on a steam bath for a period of about 8 hours. Thereaction mixture is then poured into ice water and the mixture isextracted several times with ether. The ether extracts are combined andevaporated to dryness to give 3-methyl-6-methoxyltetrulonc.

A mixture of l g. of 3-methyl-6-methoxy-l-tetralone in ml. of aceticacid is saturated with hydrogen bromide gas. The mixture is then allowedto stand for 24 hours and then the reaction mixture is concentrated. Thethus-obtained residue, 25 ml. of 95% methanol and 0.5 g. of potassiumhydroxide is refluxed for 1 hour. The reaction mixture is then pouredinto ice water and the solid which forms is collected by filtration,washed with water and dried to yield 3-,methyl-6-hydroxy-ltetralone.

A freshly prepared solution of 3 g. of vinyl bromide in 3 ml. oftetrahydrofuran is added to 0.5 g. of magnesium in 5 ml. oftetrahydrofuran to prepare a vinyl magnesium Grignard reagent. To thismixture is then added a solution of l g. of3-methyl-6-methoxy-l-tetralone in 25 ml. of tetrahydrofuran and 10 ml ofether and resulting mixture is held at room temperature for a period of24 hours, then heated at reflux for one hour and then cooled. Thereaction mixture is then poured into water, acidified with hydrochloricacid and stirred vigorously to decompose any excess Grignard reagent.The organic phase is then separated and the aqueous layer is extractedseveral times with ether. The combined ether extracts are washed withwater to neutrality, dried over sodium sulfate and evaporated to drynessto yield the crude 3-methyl-6-methoxy- 1 -vinyll -tetralol.

A mixture of l 1.8 g. of thiourea and 100 ml. of acetic acid is warmedon a steam bath until the mixture becomes homogeneous. The solution isthen cooled to room temperature and to it is then added 32 g. of 3-methyl--methoxy-l-vinyl-l-tetralol. The resulting mixture is agitateduntil the mixture again becomes homogeneous. The acetic acid is thenremoved by heating (50-60C.) under reduced pressureto afford a syrup.The syrup is poured with stirring into ml. of ether. The resultingprecipitate is collected and dried to yield2-(3-methyl-6-methoxy-l,2,3,4-tetrahydronaphthyliden)ethylisothiouronium acetate which can be recrystallized from methanolzether.

To a well-stirred solution of 16.8 g. of ethyl oz-propionyl propionatein l00 ml. of anhydrous ether is added dropwise l7 g. of bromine at sucha rate that the solution continually remains clear. After completion ofthe bromine addition, stirring is maintained for an additional 2 hours.At the end of the reaction time, the ether is evaporated under reducedpressure and the re' sulting oil is then dissolved in 65 ml. of xylene,and the resulting xylene mixture is refluxed for 17 hours. The xylenemixture is allowed to cool and then concentrated to a smaller volume andupon cooling deposited a precipitate of org-dimethyl tetraonic acidwhich is collected by filtration and recrystallized from benzene:-hexane.

To a solution of 12.5 g. of2-(3-methyl-6-methoxyl,2,3,4-tetrahydronaphthyliden)ethyl isothiouroniumacetate in a mixture of ml. ethanol, and ml. of water, is added asolution of 5.1 g. of a,7-dimethyl tetronic acid in 20 ml. ethanol.Immediately, the reaction mixture is diluted by adding an additional 80ml. of water, stirred and allowed to stand at room temperature for aperiod of 16 hours. The reaction mixture is then cooled to 5C. for 2hours, and the thus-formed precipitate collected by filtration to yieldoz-[2-(3-methyl- 6- methoxy-l ,2,3,4-tetrahydronaphthyliden)-ethyl]-a,'ydimethyl tetronic acid.

Nine grams of a-[2-(3-methyl-6-methoxy-l,2,3,4-tetrahydronaphthyliden)-ethyl]-a,y-dimethyl tetronic acid and 460 mg. ofp-toluenesulfonic acid in ml. of benzene is heated at reflux for fourhours, during which time water is continuously removed from the reactionmixture by a Dean-Stark trap. After cooling, the reaction mixture isfiltered through a short column of silica gel and evaporated underreduced pressure to yield 3-methoxy-7, l 5-dimethyl l6-oxaestral,3,5(lO),8,l4-pentaen-l7-one which is recrystallized fromether.

A mixture of 0.5 g. of 3-methoxy-7,l5-dimethyl-l6-oxaestra-l,3,5(l0),8,l4-pentaen-l7-one and 5 mg. of 5%palladium-on-charcoal catalyst. and 75 ml. of xylene is heated at refluxfor 36 hours. The mixture is then cooled, filtered to remove thecatalyst and the filtrate is evaporated under reduced pressure to yielda residue 1 6-oxa-estra-1 ,3,5

containing predominantly 3-methoxy-7, l 5-dimethyl-6-oxaestra-l,3,5(l),6,8,l4-hexaen-l7-one and a small amount of3-methoxy-7, 1 S-dimethyl-l 6-oxal 4B-estral,3,5(10),6,8-pentaen-l7-one.The residue is purified by preparative thin layer chromatography andcrystallized from methanol to yield 3-methoxy-7,l5-dimethyl-(l0),6,8,l4-hexaen-l7-one. 3- methoxy-7, l S-dimethyll 6-oxaestra-l ,3,5( l0),8, l 4- pentaen-l 7-one, 0.4 g. of maleic acid and 0.25 g. of 5%palladium-on-charcoal catalyst and 75 ml. of benzene is heated at refluxfor about 24 hours. The mixture is then cooled to room temperature andfiltered. The filtrate is then washed with dilute aqueous sodiumbicarbonate solution, dried and evaporated to yield 3-methoxy-7,l5-dimethyl-l6-oxaestra-l,3,5(10),6,8,l4- hexaen-l7-one whichis crystallized from methanol.

A mixture of 250 mg. of3-methoxy-7,l5-dimethyll6-oxaestra-l,3,5(l0),6,8,l4-hexaen-l7-one in 25ml. of absolute ethanol and ml. of 1N aqueous sodium hydroxide solutionis allowed to stand at room temperature for 24 hours. The reactionmixture is then filtered and the thus-collected crystalline residue iswashed with water and dried to yield the sodium salt of cis 7- methoxyl-acetyl-2, l O-dimethyl-l ,2,3 ,4 -tetrahydrophenanthrene-Z-carboxylicacid.

A mixture of 307 mg. of sodium salt of cis 7- methoxyl-acetyl-2, lO-dimethyl-l ,2,3 ,4- tetrahydrophenanthrene-Z-carboxylic acid, 1 ml. ofmethyl iodide and 7 ml. of dimethylacetamide is stirred in the dark for5 hours. Then, excess methyl iodide is removed by evaporation underreduced pressure. The reaction mixture is then poured into water and themixture extracted several times with ether. The ether ex-' tracts arecombined, washed with water, and then dilute aqueous sodium thiosulfatesolution, dried and evaporated to furnish the methyl ester of cis 7-methoxyl-acetyl-2, l O-dimethyl-l ,2,3 ,4-tetrahydrophenanthrene-2-carboxylic acid which can be crystallized frombenzene-hexane.

Into the cathode compartment of a divided electrolysis cell providedwith a cellulose dialysis membrane, lead electrodes (each electrodemeasuring 2 cm. X 5 cm. X 1.6 mm.) and a stirrer, there is added 20 mg.of methyl ester of cis7-methoxy-l-acetyl-2,IO-dimethyll,2.3,4-tetrahydrophenanthrene-Z-carboxylicacid and a mixture of ml. of dioxane and 15 ml. of 10% aqueous sulfuricacid (by weight). An additional amount of a mixture of 15 ml. of dioxaneand 15 ml. of 10% aqueous sulfuric acid is added to the cell. A currentdensity of 0.02 amps/cm. is applied for a period of 5 hours. Thereaction mixture is then removed from the cell and concentrated underreduced pressure to a small volume which is then extracted several timeswith ether. The ether extracts are combined, washed with water and a 5%aqueous sodium bicarbonate solution, dried and evaporated to dryness tofurnish the methyl ester of cis acidified by the addition of diluteaqueous hydrochloric acid and extracted several times with the ethylacetate.

EXAMPLE 1 Liquid ammonia which has been dried over sodium metal anddistilled (600 ml.), 300 ml. dry tetrahydrofuran, and 150 ml. of dryethanol are mixed together 10 with stirring. Ten g. ofla-ethyl-Za-carboxy-2/3-methyl- 7-methoxy-l,2,3,4-tetrahydrophenanthrene(cis bisdehydrodoisynolic acid methyl ether) are then added to themixture while continuing the stirring. To the resultant mixture areadded 54 g. of lithium wire in ca.

15 2.0 g. portions with concommitant addition of 500 ml.

of ethanol in ml. portions over a total period of ca. 24 hours whilemaintaining the reaction mixture at reflux (ca. 20). After this period,the ammonia is allowed to evaporate and 2 l. of a saturated, aqueoussolution of sodium dihydroorthosphosphate is added to the concentrate.The resultant mixture is then extracted with ethyl acetate and theextract is dried over sodium sulfate and evaporated. The concentrate,after evaporation, is then fractionally crystallized from ethyl acetateto provide the la-ethyl-2a-carboxy-2B-methyl- 7-methoxy-l ,2,3,4,5 ,8,9,l 2a-octahydrophenanthrene product.

Pyridine (0.5 ml.) and chloroform (2 ml.) are mixed and maintainedtogether at room temperature. To the resultant mixture are added mg. ofla-ethyl-Zacarboxy-2fl methyl-7-methoxyl ,2,3 ,4,5 ,8,9,12oz.octahydrophenanthrene, while maintaining the mixture at roomtemperature. After the addition, the resultant mixture is cooled to C.with stirring. While continuing the stirring of the cooled mixture, 87mg. of pyridinium hydrobromide perbromide are added. After -theaddition, the reaction mixture is allowed to warm to room temperaturewith stirring. After this time, the reaction solution is poured into 5%l-lCl ice water. The resultant mixture is extracted with ethyl acetate,washed with water and then saturated NaCl and evaporated. Theconcentrate after evaporation is recrystallized from methanol to providethe la-ethyl-Za- 45 carboxy-2B-methyl-7-methoxy-l ,2,3,4,9,l2a-hexahy-55 fied mixture extracted with ethyl acetate. The extracts are driedover magnesium sulfate and evaporated to provide a concentrate which isfractionally crystallized from methanol/H O to obtain thela-ethyl-2a-carboxy- 2,8-methyl-7-hydroxy-l ,2,3,4,9,l Za-hexahydro- 6Ophenanthrene product.

EXAMPLE 2 Liquid ammonia which has been dried over sodium metal anddistilled (600 ml.), 300 ml. dry tetrahydro- 5 furan, and ml. of dryethanol are mixed together with stirring. Ten g. ofla-ethyl-Za-carboxy-ZB-methyl- 7-methoxyl,2,3,4-tetrahydrophenanthene(cis bisdehydrodoisynolic acid methyl ether)are then added to the mixture while continuing the stirring. To theresultant mixture are added 54 g. of lithium wire in ca. 2.0 g. portionswith concommitant addition of 500 ml. of ethanol in 20 ml. portions overa total period of ca. 24 hours while maintaining the reaction mixture atreflux (ca. -20). After this period, the ammonia is allowed to evaporateand 2 l. of a saturated, aqueous solution of sodiumdihydroorthophosphate is added to the concentrate. The resultant mixtureis then extracted with ethyl acetate and the extract is dried oversodium sulfate and evaporated to provide the 1201 and 12B epimers ofla-ethyl-Za-carboxy-ZB-methyl-7-methoxy-1,2,3,4,5,8,9,12-octahydrophenanthrene.

Pyridine (0.5 ml.) and chloroform (2 ml.) are mixed and maintainedtogether at room temperature. To the resultant mixture are added 75 mg.of the 120: and 12,8 epimers ofla-ethyl-2acarboxy-2,B-methyl-7-methoxyl,2,3,4,5,8,9,l2-oetahydrophenanthrene,prepared as described above, while maintaining the mixture at roomtemperature. After the addition, the resultant mixture is cooled to-80C. with stirring. While continuing stirring of the cooled mixture, 87mg. of pyridiuium hydrobromide perbromide are added. After the addition,the reaction mixture is allowed to warm to room temperature withstirring. After this time, the reaction solution is poured into HCl icewater. The resultant mixture is extracted with ethyl acetate, washedwith water and then saturated NaCl and evaporated to provide the 12a and12B epimers of lOl-BthYl- 2oz-carboxy-2B-methyl-7-methoxy-l,2,3,4,9,12-hexahydrophenanthrene. The concentrate after evaporation iscrystallized from methanol to provide thelaethyl-Za-carboxy-2B-methy1-7-methoxy 1 ,2 ,3 ,4 ,912a-hexahydrophenanthrene product. The mother. liquor is subjected tothin-layer chromatography to obtain thela-ethyl-Za-carboxy-2B-methyl-7-methoxyl,2,3,4,9, l2B-hexahydrophenanthrene.

The 1a-ethyl-Za-carboxy-ZB-methyl-7-methoxy- 1,2,3,4,9, l2a-hexahydrophenanthrene thus prepared is treated with lithium iodide asdescribed in Example 1 to obtain the 1a-ethyl-2a-carboxy-2B-methyl-7-hydroxy-l ,2,3,4,9,1Za-hexahydrophenanthrene product.

EXAMPLE 3 A mixture of 1a-ethyl-Za-carbomethoxy-2B-ethy1-7-methoxy-l,2,3,4-tetrahydrophenanthrene (104 mg.) in 300 mg. oft-butanolis dispersed in a mixture of 25 ml. of ammonia and ml. oftetrahydrofuran with stirring. Lithium wire mg.) is then added to theresultant solution in a portion-wise fashion at reflux. After the bluecolor of the resultant mixture has faded (about minutes), the ammonia isallowed to evaporate. After evaporation period, water and diethyl etherare added to the resultant mixture. The ether layer is separated andwashed with water, dried and evaporated to obtain a residue which isrecrystallized from ether hexane to obtain thela-ethyl-2a-hydroxymethyl-2B-methyl-7-methoxy-l,2,3,4,5,8-hexahydrophenanthrene product.

A solution is prepared by dispersing 500 mg. of1aethyl-2a-hydroxymethyl-2B-methy1-7-methoxy-1,2,3,4,5,8-hexahydrophenanthrene in 100 ml. of tetrahydrofuran and 100ml. of ammonia. Lithium wire (500 mg.) and 10 ml. of t-butanol are addedportionwise thereto over a period of 5 days at a rate sufficient tomaintain a blue color. After the blue color of the reaction mixture hasfaded, water and ether are added.

The ether layer is separated and washed with water. dried and evaporatedto provide an isomeric mixture ofla-ethyl-2a-hydroxymethyl-2B-methyl7-methoxy- 1,2,3 ,4,5 ,8 ,9, 1Z-octahydrophenanthrene.

5 The epimeric mixture of 1a-ethyl-Za-hydroxymethyl-2Bmethyl-7-inethoxy-1,2,3,4,5,8,9,12- octahydrophenanthrene (103 mg.) isdispersed in 1 ml. of pyridine and 100 mg. of pyridinium hydrobromideperbromide in 0.5 m1. of pyridine are added dropwise.

10 The pyridine is evaporated by passing a stream of nitrogen throughthe reaction mixture and the resultant residue partitioned betweendiethyl ether and water. The ether extracts are washed with water, driedand evaporated to obtain the la-ethyl-Za-hydroxymethyll52B-methyl-7-methoxy-l,2,3,4,9,12-hexahydrophenanthrene epimericproducts. The residue is subjected to thin-layer chromatography toseparate the --1a-ethyl-Za-hydroxymethyl- 2B-methyl-7-methoxy- 1,2,3,4,9,l 2a-hexahydro- 20 phenanthrene product and the corresponding126 product.

Similarily as described above, the 12a epimer in theZa-hydroxymethyl-l,2,3,4,5,8,9,12- octahydrophenanthrene series isisolated.

hydroxy-l,2,3,4-tetrahydrophenanthrene in 15 ml. of benzene. About 1 ml.is removed by distillation to remove moisture and 0.4 g. ofp-toluenesulfonyl chloride is added to the cooled solution. This mixtureis allowed to stand at room temperature for 4 days, and is then washedwith aqueous sodium carbonate solution and water, dried and evaporated.The residue is chromato-- graphed on neutral alumina, eluting withhexane, to yield let-ethyl- 2a-carbotetrahydropyran-2-yloxy-2B-methyl-7-tetrahydropyran-2'-yloxy-1 ,2,3,4-tetrahydrophenanthrene which isrecrystallized from pentane.

la'Ethyl-2 a-carbotetrahydropyran-Z -yloxy-2B-methyl-7-tetrahydropyran-2-yloxy-1,2,3 ,4-tetrahydrophenanthrene isreacted with 100 equivalents of sodium metal and ammonia in the presenceof t-butanol as otherwise set forth in Example 3 to obtain first thela-ethyI-Za-hydroxymethyl-2/3-methyl-7- tetrahydropyran-2'-yloxy-l,2,3,4,5,8-hexahydrophenanthrene product and second thela-ethyl-2ahydroxymethyl-2,8-methyl-7-tetrahydropyran-2'-yloxy1,2,3,4,5.8,9,1Z-octahydrophenanthrene products. The isomeric mixture ofthe latter product is reacted with pyridinium hydrobromide perbromide asset forth in Example 3 to obtain the 1a-ethyl-2a-hydroxymethyl-2,8-methyl-7-tetrahydropyran-2 yloxy-l ,2.3 ,4,9,12-hexahydrophenanthrene products. Each isomer can be treatd in accordancewith the procedure of Example 1 to provide the1a-ethyl-Za-hydroxymethyl-Zfimethyl 7-hydroxy-l,2,3,4,9,12-hexahydrophenanthrene products.

In a manner similar to that set forth above, la-ethyl-2a-hydroxymethyl-2B-methyl-7-tetrahydropyran-Z'- yloxy-l,2,3,4,9,12-hexahydrophenanthrene product is obtainable by employing thecorresponding methyl, ethyl, n-propyl, and n-butyl esters in lieu of thecarbo ester starting material.

EXAMPLE A mixture of l g. of la-ethyl-2a-hydroxymethyl-2B-methyl-7-methoxyl ,2,3 ,4,9, l 2-hexahydrophenanthrene, 4 ml. ofpyridine and 2 ml. of acetic anhydride is allowed to stand at roomtemperature for hours. The mixture is then poured into ice water and thesolid which forms is collected by filtration, washed with water anddried to yield la-ethyl-Za-acetoxymethyl- 2,B- methyl-7-methoxy-l ,2,3,4,9, l 2-hexahydrophenanthrene which may be further purified throughrecrystallization from acetonezhexane.

In like manner, the Za-propionyloxymethyl, -butroyloxymethyl,-caproyloxymethyl, and -trimethylacetoxymethyl compounds otherwisecorresponding to the acetoxymethyl product of the foregoing paragraphare prepared by using the corresponding acylating agent. In like manner,the other acyloxymethyl compounds of the present invention are preparedby utilizing the corresponding acylating agent.

Two milliliters of dihydropyran are added to a solution of 1 g. ofla-ethyl-Za-hydroxymethyl-2B-methyl-7-methoxy-l,2,3,4,9,l2-hexahydrophenanthrene in 15 ml. of benzene. About1 ml. is removed by distillation to remove moisture and 0.4 g. ofp-toluenesulfonyl chloride is added to the cooled solution. This mixtureis allowed to stand at room temperature for four days,

and is then washed with aqueous sodium carbonate solution and water,dried and evaporated. The residue is chromatographed on neutral alumina,eluting with hexane, to yield la-ethyl-2a-tetrahydropyran-2yloxymethyl-2B-methyl-7-methoxyl ,2,3,4,9, l 2-hexahydrophenanthrenewhich is recrystallized from pen tane.

By employing the method of the preceding paragraph using dihydrofuran inlieu of dihydropyran, there is prepared the correspondingla-ethyl-Zwtetrahydrofuran- 2-yloxymethyl-2B-methyl-7-methoxy-l,2,3,4,9,l 2- hexahydrophenanthrene product. Similarly, thelotethyl-2a-(4-methoxy-tetrahydropyran-4'-yloxymethyl)-2B-methy1-7-methoxy-l,2,3,4-tetrahydrophenanthreneproduct is prepared by utilization of the foregoing procedure employing4-methoxy-5,6- dihydro-2H-pyran in lieu of dihydropyran.

A solution of one chemical equivalent of la-ethyl-2a-hydroxymethyl-2B-methyl-7-methoxy-1,2,3,4,9,l2- hexahydrophenanthrenein ml. of benzene is heated to reflux and about 2 ml. removed bydistillation to eliminate moisture. The mixture is cooled to roomtemperature and two chemical equivalents of sodium hydride are added,followed by the dropwise addition of two chemical equivalents ofcyclopentyl bromide in 10 ml. of benzene over a period of 20 minutes.The mixture is allowed to reflux for 20 hours after which time theprecipitate of sodium bromide is removed by filtration and the organicphase dried and evaporated to yieldla-ethyl-2a-cyclopentyloxymethyl-2B-methyl-7- methoxyl ,2,3,4,9, l2-hexahydrophenanthrene which is further purified upon recrystallizationfrom pentane.

Alternatively, the ethers ofla-ethyl-Zahydroxymethyl-2/3-methyl-7-methoxy-1,2,3,4-tetrahydrophenanthrene are prepared in accordance with paragraphs3, 4 and 5 of this example and the resultant compounds are treated inaccordance with the procedures of Example 1 above to prepare the 20:-tetrahydropyran-Z'-yloxymethyl-tetrahydrofuran-2'- yloxymethyl,-4'-methoxy-tetrahydropyran-4- yloxymethyl, and -cyclopentyloxymethylcompounds in the la-ethyl-ZB-methyl-7-methoxy-l ,2,3,4,9. l2-hexahydrophenanthrene series.

Similarly, the foregoing methods are used to prepare the correspondingC-7 esters and ethers of the l,2,3,4,- 9,12-hexahydrophenanthreneproducts hereof.

The methods of the foregoing procedures can be practiced utilizing a7-tetrahydropyran-Z-yloxy compound in lieu of the 7-methoxy startingcompound set forth therein to provide the corresponding 7-tetrahydropyran-Z'-yloxy-l ,2,3,4,9,1 2-hexahydrophenanthrene product.These compounds can then be hydrolyzed as set forth in paragraph 3,Example 1.

EXAMPLE 6 i Twenty ml. of liquid ammonia, 10 ml. of tetrahydrofuran, and5 ml. of ethanol are mixed together. To the resultant mixture are added300 mg. ofla-ethyl-2aacetoxymethyl-2,B-methyl-7-methoxy-1,2,3,4-tetrahydrophenanthrenewith stirring. To the resulting mixture are added 50 equivalents ofsodium metal in a portionwise fashion and with stirring. After theaddition period of about 72 hours, the reaction mixture is worked up asset forth in Example 1 to provide thelaethyl-2ahydroxymethyl-2B-methyl-7-methoxy-l,2,3,4,5,8,9,l2-octahydrophenanthrene products. The use of potassium metal in t-butanoland lithium metal in isopropanol affords similar results.

The latter product is treated with pyridinium hydrobromide perbromide toobtain the correspondinglaethyl-2a-hydroxymethyl-2B-methyl-7-methoxyl,2,3,4,9,12-hexahydrophenanthreneproducts.

EXAMPLE 7 To a solution of 3 g. of la-ethyl-Za-carboxy-ZB-methyl-7-methoxy-l,2,3,4,9,12a-hexahydrophenanthrene in 50 ml. ofmethylene chloride are added an excess of diazomethane in ether(obtained from nitrosomethylurea) and a few drops of methanol. Thereaction mixture is maintained at room temperature for 18 hours and theexcess reagent is then decomposed by the addition of acetic acid. Theresulting mixture is poured into water and the organic layer isseparated, washed with water to neutrality and evaporated to dryness toyield la-ethyl-Za-carbomethoxy-2B-methyl-7-methoxy-l,2,3,4,9,lZa-hexahydrophenanthrene product.

In a manner similar to the above, the other correspondingZa-carboalkyloxy compounds of the present invention are prepared.

EXAMPLE 8 To a solution of 14.2 mg. ofla-ethyl-2ahydroxymethyl-2B-methyl-7-methoxy-l,2,3,4,9,l2a'hexahydrophenanthrene in ml. of dry dimethylsulfoxide is added asolution of 49.6 mg. of dicyclohexylcarbodiimide in 300g ofdimethylsulfoxide, followed by the addition of a solution of 2,1. oftrifluoroacetic acid, 3.8;1. of pyridine and 50p. of dimethylsulfoxide.After reaction, the mixture is partitioned between water and diethylether. The ether extracts are washed with water, dried and evaporated.The residue is subjected to thin-layer chromatography to obtain thelaethyl-Za-formyl-2B-methyl-7-meth0xy-l ,2,3,4,9, l 2&-hexahydrophenanthrene product.

EXAMPLE 9 To a stirred solution of l g. of lB-ethyl-Za-formyl-ZB-methyl-7-cyclopentyloxy-1,2,3,4,9,l2-hexahydrophenanthrene in 10 ml.of acetone, cooled to C., is added under nitrogen a solution of 8Nchromic acid (prepared by mixing 26 g. of chromium trioxide with 23 ml.of concentrated sulfuric acid and diluting with water to 100 ml.) untilthe color of the reagent persists in the mixture. The mixture is thenstirred for 5 minutes at O-5C. and diluted with water. The solid whichforms is collected by filtration, washed with water and dried undervacuum to yield lB-ethyl-2a-carb0xyl2/3- methyl-7-cyclopentyloxyl ,2,3,4,9, l 2-hexahydrophenanthrene which may be further purified byrecrysl5 tallization from acetone: hexane.

EXAMPLE 10 To a solution of IO g. of la-ethyl-2a-carboxy-2B,l0--carboxyacetone:hexane dimethyl-7-methoxy 2Q l,2,3,4,9,lZ-heXahydrophenanthrcne in 200 ml. of ethanol is added the theoreticalamount of potassium hydroxide dissolved in 200 ml. of 90% ethanol. Thereaction mixture is then concentrated in vacuum giving potassiumlmethyl-2B,lO-dimethyl-7-methoxy- 25 12.3.4.9, l2-hexahydrophenanthrene-20z-carboxylate.

In accordance with the foregoing methods, the following are prepared:

la-methyl-2a-carboxy-2B-ethyl-7-methoxyl,2,3,4,9,l2-hexahydrophenanthrene,

l,8-ethyl-2a-carboethoxy-7-methoxyl O-methyll,2,3.4,9, l2-hexahydrophenanthrene,

la-ethyl-2a-carbo-n-propoxy-ZB-methyl-7-(4'-methoxytetrahydropyran-4-yloxy)-l ,2,3,4,9, l 2-hexahydrophenanthrene,

l B-ethyl-2a-tetrahydropyran-2 'yloxy-2B-methyl-7- hydroxy-- l ,2,3,4,9,l 2-hexahydrophenanthrene,

la-methyl-Za-formyl-2,B-ethyl-7-propionyloxy- 1,2,3 ,4,9, l2-hexahydrophenanthrene,

sodium la-ethyl-ZB-methyl-7-methoxy-l ,2,3,4,9,l2- 40hexahydrophenanthrene-Za-carboxylate,

l,B-ethyl-2a-carbo-n-butoxy-ZB-ethyl-7-hydroxyl,2,3.4,9,l2-hexahydrophenanthrene,

1121,23,] 0-trimethyl-2a-carboxy-7-hydroxyl,2,3,4,9,12-hexahydrophenanthrene.

1B,lO-dimethyl-2a-pentanoyloxymethyl-2B-ethyl-7- cyclopentyloxyl,2,3,4,9, l 2-hexahydrophenanthrene,l,B,2B-diethyl-Za-cyclopentyloxymethyl-7-acetoxy-1,2,3,4,9,l2-hexahydrophenanthrene,

potassium la-ethyl-ZB-methyl-7-acetoxyl,2,3,4,9, l2-hexahydrophenanthrene-2a-carboxylate,

lB-ethyl-Za-carboxy-2/3-methyl-7-tetrahydropyran- 2 '-yloxy-l ,2,3,4,9,l 2-hexahydrophenanthrene,

lB-methyl-2a-formyl-2B-ethyl-7-ethoxyl,2,3,4,9, l2-hexahydrophenanthrene,

lB-ethyl-Za-hydroxymethyl-2,8-methyl-7-n-propoxy- R is methyl or ethyl:

R is hydroxymethyl or the hydrolyzable hydrocarbon carboxylic acidesters thereof wherein the carboxylic acid moiety has from 2 to 14carbon atoms;

R is methyl or ethyl;

R is lower alkyloxy wherein the alkyl moiety has from 1 to 6 carbonatoms, hydroxy, the hydrolyzable hydrocarbon carboxylic acid esters ofsaid hydroxy group wherein the carboxylic acid moiety has from 2 to 14carbon atoms, tetrahydropyran- 2'-yloxy, tetrahydrofuran-Z-yloxy, 4-methoxytetrahydropyran-2'-yl.oxy, or cyclopentyloxy; and R is hydrogenor methyl. 2. A C-lZa compound according to claim 1. 3. A compoundaccording to claim 1 wherein R is ethyl; R is methyl; and R is loweralkyloxy.

4. A compound according to claim 3 wherein R is hydrogen.

5. A compound according to claim 4 wherein R hydroxymethyl.

6. The compound according the claim 5 wherein R is methoxy.

7. A C-l2a compound according to claim 1 wherein R is ethyl; R ishydroxymethyl; R is methyl; R is lower alkyloxy; and R is hydrogen.

8. The compound according to claim 7 wherein R is methoxy;la-ethyl-2a-hydroxymethyl-2B-methyl-7- methoxy-l ,2,3,4,9, l2a-hexahydrophenanthrene.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Q Patent 3,865,883Dated February 11, 1975 Invent0r(s)JOHN A. EDWARDS et al It is certifiedthat error appears in the above-identified patent Q and that saidLetters Patent are hereby corrected as shown below:

Column 2, line 4, change "symmetry to asymmetry--.

Column 5, line 39, change "quences In" to quences. In.

I Column 7, line 5, change R to R e 2' 2 Column 7, line 22, change "R toR Column 8, line 9, change "ethers to ethers)-.

Column 16, lines 59, 60 and 61, change "11" to --ul-. 8

Column 17, line 12, change "carboxy l26" to carboxy-2B- Column 17, line20, delete "carboxy-acetone:hexane".

Column 18, line 4, change "2c" to 26- C Signed and Scaled this ninth DayOf September 1975 [SEAL] e I Altesr:

RUTH C. MASON C. MARSHALL DANN Arresting Officer (mnml'ssiuneruj'Palents and Trademarks Q

1. A PROCESS FOR PREPARING GLYOXAL WHICH COMPRISES IN THE
 1. A COMPOUNDSELECTED FROM THE GROUPS OF COMPOUNDS REPRESENTED BY THE FOLLOWINGFORMULA: PRESENCE OF WATER REACTING CHLORACETALDEHYDE WITH A DIALKYLSULFOXIDE, EACH OF SAID ALKYL GROUPS, WHICH MAY BE THE SAME OR
 2. A C-12Alpha compound according to claim
 1. 3. A compound according to claim 1wherein R1 is ethyl; R3 is methyl; and R4 is lower alkyloxy.
 4. Acompound according to claim 3 wherein R5 is hydrogen.
 5. A compoundaccording to claim 4 wherein R2 is hydroxymethyl.
 6. The compoundaccording the claim 5 wherein R4 is methoxy.
 7. A C-12 Alpha compoundaccording to claim 1 wherein R1 is ethyl; R2 is hydroxymethyl; R3 ismethyl; R4 is lower alkyloxy; and R5 is hydrogen.
 8. The compoundaccording to claim 7 wherein R4 is methoxy; 1 Alpha -ethyl-2 Alpha-hydroxymethyl-2 Beta -methyl-7-methoxy-1,2, 3,4,9,12 Alpha-hexahydrophenanthrene.